1. Field of the Invention The invention relates to the field of pharmacy and drug formulation. The invention relates particularly to a powder formulation of a therapeutically active substance for administration to a patient by inhalation.
2. Description of the Related Art
Dry powder inhalers (DPI's) are on the market since the Spinhaler was introduced nearly 30 years ago. Basically, DPI's consist of a powder formulation, a dose (measuring) system and a disintegration principle.
The powder formulation contains a therapeutically active ingredient, typically a drug, in the required size range for effective deposition in the lower respiratory tract (target area) of the user of the inhaler. The required size range is obtained either directly from precipitation, spray drying or with comminution techniques, like jet milling (fluid energy milling) or ball milling.
Different effective particle diameters or size ranges have been described for solid drug particles for inhalation. Particles exceeding 5 μm are believed to deposit mainly in the oropharynx and the efficiencies of deposition mechanisms have been reported to confine the minimum diameter for aerosol particles to 0.5 μm. The diameters of spherical particles below which significant deposition in the head region during oral inhalation (at 60 l/min) is avoided are calculated to be 2.4 micron for particles with a density of 1.0 g/cm3, respectively 1.4 micron for particles with a density of 1.5 g/cm3. European Patent Application 0 876 814 claims that only particles <2 μm can reach the alveolar region.
It is difficult to compare the different studies disclosed in the art with each other, because of the different definitions used. In the early publications, recommended particle sizes often refer to geometric diameter or equivalent volume diameter (De). In more recent studies, the mass median aerodynamic diameter is often described, but sometimes this MMAD makes a correction for particle density (ρp) only, whereas MMAD (by definition) should take account of the dynamic shape factor (χ) as well:Da=De(ρp/χ)0 5 
Edwards et al. (Science 276 (1997) 1868-1871) described a new type of inhalation aerosol consisting of large particles (>5 μm, up to 20 microns) with low densities (ρ<0.4 g/cm3), having the same aerodynamic diameters as solid particles with unit density (or higher) and much lower geometric diameters. They claim that these so-called ‘large porous particles’ penetrate deeply in the lungs. Because of their size they escape the lungs' natural clearance mechanisms (e.g. phagocytic clearance by macrophages in the alveoli), and increase both the bioavailability (as achieved for testosterone) and duration of the therapeutic effect from sustained release particles (as achieved for insulin) composed of biodegradable polymers. The authors also claim that large porous particles can be aerosolized from a DPI more efficiently than smaller nonporous particles, resulting in higher respirable fractions of the inhaled therapeutics. This is explained by a much higher agglomeration tendency of small, high density particles with high surface-to-volume ratio, which causes these particles to exit the DPI as small agglomerates rather than as primary entities.
Achieving a high dose reproducibility with micronized powders is impossible because of their poor flowability and extreme agglomeration tendency. To give the most effective dry powder aerosol, the particles should be large while in the inhaler, but small when discharged into the respiratory tract. Therefore, an excipient (such as lactose or glucose) is generally added either as a diluent (e.g. for preparing spherical pellets) or as an excipient (e.g. for preparing adhesive mixtures).
In adhesive mixtures, the fine drug particles are distributed homogeneously over the surface area of the large excipient crystals, held in position by mild drug-to-excipient interaction forces (e.g. van der Waals forces), that must be exceeded during inhalation by removal forces for fine particle detachment, thus, to transport only the drug particles into the lower respiratory tract. Only two exceptions are known: the Fisons Spincaps, containing pure DSCG and the ASTRA Turbuhaler, containing pure budesonide or terbutalin sulphate.
The use of substantial amounts of lactose (or glucose) in inhalation powders is arguable, however, because of possible irritation during inhalation, which may result in coughing and bronchoconstriction. Drug particles, adhering to coarse lactose crystals that are deposited in the mouth and throat, may result in local (or systemic) side effects, especially the cortico steroids. Recently, Higham et al. (Clin. Pharmacol. 40 (1995) 281-282) investigated the determination of excipient lactose from the Diskhaler by 20 healthy volunteers and found that more than fifteen volunteers (i.e. >75%) were able to sense (taste or feel) a dose of only 3 mg excipient substance. Even the inhalation of 1 mg lactose was still sensed by 8 subjects. WO 97/03649 refers to physiological benefits from introducing as little powder as possible to the lungs, especially material other than the active ingredient to be inhaled.
The desired type and size fraction of (excipient) lactose varies with specific demands regarding powder disintegration and powder flow; both being dependent on inhaler design as well. Mostly, crystalline alpha lactose monohydrate is used as excipient. Timsina et al. (Int. J. Pharm. 101 (1994) 1-13) explained that the excipient particles, usually lactose, are incorporated with the micronized drug powder to make it less cohesive and more freely flowing, thus making it easier to handle.
Several studies are known in which a positive effect from the presence of fine or micronized lactose in inhalation powders on fine particle yield from the DPI is claimed. U.S. Pat. No. 5,478,578 quotes that the inhalable active substance content is negatively affected by a coarse excipient as proposed in DE-A-1792207. In said U.S. patent it is therefore stated that the inhalable portion of the active substance in inhalation powders can be controlled within wide limits (while keeping good accuracy of metering) by combining the micronized active substance with suitable quantities of a mixture of acceptable excipients. It is disclosed that one component of the mixture has to have a mean particle size of less than 10 μm, whereas the other component has to have a mean diameter of greater than 20 μm (generally below 150 μm and preferably below 80 μm). The weight ratios of the fine and coarse excipient are to be between 1:99 and 95:5; preferably between 5:95 and 70:30 and especially between 10:90 and 50:50.
A few studies are known in which modification of the surface morphology of lactose excipient particles is described for maximal drug particle detachment from the excipient crystals during inhalation (e.g. International patent publications WO 95/11666, WO 96/23485 and WO 97/03649).
In WO 95/11666 it is described that the surface of an excipient particle is not smooth, but has asperities and clefts with higher surface energy. Drug particles are attracted to and adhere to these areas more strongly than on other sites of the excipient surface. As a consequence, drug particle detachment during inhalation and thus, respiratory deposition are reduced. The asperities are explained in terms of adhering fine grains. Treatment consists of gently milling the excipient particles, preferably in a ball mill at a low number of revolutions per minute (e.g. 6), for about six hours. During this treatment, asperities (small grains) are dislodged from the excipient surface and attracted to the high energy sites in clefts but the size of the excipient particles is not substantially changed. As a result of the treatment, the total number of active sites on the excipient particles is strongly reduced. The treatment may be carried out before the active particles are added or in the presence of active particles.
WO 96/23485 describes the use of small amounts of additive particles for the occupation of the active sites of excipient particles. The weight percent of the additive particles must not be too high (for most materials less than 2%) in order to avoid segregation of the mixture with the active ingredient. The additive particles are of an anti-adherent or anti-friction material (e.g. magnesium stearate, leucine, lecithin, talc, starch and silicon dioxide) or a combination of more materials. It is particular advantageous for the additive material to comprise an amino acid, because of observed high respirable drug fractions, little segregation and little amino acid being transported into the lower lung.
WO 97/03649 expands the application of additives to inhalation powders containing advantageously 70%, to most preferably 99% (by weight) of the active material. 90% (by weight) of the particles in this powder should advantageously be smaller than 63 μm and more preferably smaller than 10 μm. The additive material may be present in the powder both in the form of small particles and in the form of a coating on the surfaces of the particles of active material. It is explained that the additive material interferes with the weak bonding forces (e.g. van der Waals and Coulombic forces) between the drug particles as weak links or chain breakers, helping to keep them separated. The same substances are proposed as in WO 96/23485. Both patents describing the use of additives have been worked out in the so-called Passcal™ Technology (corrasion process) as applied by RP Scherer AG (Baar, Switzerland, 1996). The deposition of additives in the lower respiratory tract has yet unknown safety aspects however.
ASTRA DRACO for their latest formulations (e.g. with salbutamol sulfate and formoterol fumarate) use only micronized lactose as excipient (NL-A-10.08019). They described the preparation of spherical pellets, with a bulk density between 0.28 and 0.38 g/cm3, containing micronized drug and a mono-, di- or polysaccharide (preferably alpha lactose monohydrate), both in size fractions <10 μm (preferably 1-7 μm), in order to reduce dose variation. The use of micronized lactose is preferred to much coarser lactose crystals because of a much better dispersion of the drug, observed during in vitro testing of the formulations. Pellet size is in the range 100-2000 μm (preferably between 100 and 800 μm.
Typically, DPI's, contain a dose system, which contains the powder formulation either in bulk supply or quantified into individual doses stored in unit dose compartments, like hard gelatin capsules or blisters. Bulk containers are equipped with a measuring system operated by the patient in order to isolate a single dose from the powder immediately before inhalation. High dose reproducibility requires excellent content uniformity and reproducible dose weighing of the powder into the dose system as well as complete discharge of this dose system by the inspiratory air during inhalation. Flow properties of the powder formulation, and long term physical and mechanical stability in this respect, are more critical for bulk containers than they are for single unit dose compartments. Good moisture protection can be achieved more easily for unit dose compartments (like blisters), however.
The disintegration principle of the DPI generates primary drug particles or small agglomerates from the powder formulation during inhalation by disrupting spherical pellets or detaching small drug particles from the much larger excipient crystals. The amount of fine drug entities discharged from the inhaler's mouthpiece during inhalation is largely dependent on the interparticulate forces in the powder formulation (between drug and drug particles or between drug and excipient particles) and the efficiency of the disintegration principle of the DPI to utilize the energy from the inspiratory air stream (at a given flow rate). Most of the presently marketed DPI's containing adhesive mixtures, deliver a maximal fine particle fraction of 20-25% of the nominal dose. DPI's with spherical pellets have higher fine particle outputs, up to a maximum of 40-50% of the nominal dose (above approx. 40-50 l/min for the Turbuhaler and 120 l/min for the Spinhaler).
In U.S. Pat. No. 5,301,666, a specific DPI for use by asthma patients has been disclosed. This DPI comprises a cyclone chamber. The particles of active substance which the asthma patient inhales contain virtually no larger-sized constituents or particles. 90-95% of the particles released are of respirable size.